Chapter 21: Carbxylic Acid Derivatives: Nuclephilic Acyl Substitutin Reactins 21.1 Naming Carbxylic Acid Derivatives Naming Acid Halides, RCOX Naming Acid Anhydrides, RCO 2COR Naming Esters, RCO 2R 1. Name the alkyl grup - ethyl 2. Name the acyl grup - acetate (ethanate) Replace ic acid with ate Naming 1 Amides, RCONH 2 Fr all 1 amides Replace ic acid, ic acid, ylic acid with amide Naming 2 and 3 Amides 1. Name the alkyl grup (grups) bnded t N first 2. Use N as a prefix befre each alkyl grup name 3. In a 3 amide, if tw grups are the same, use N,N-dialkyl Sme Interesting Amides Thiesters, RCOSR Acyl Phsphates, RCO 2PO 3 2- and RCO 2PO 3R
21.10 Spectrscpy f Carbxylic Acid Derivatives Infrared Spectrscpy IR Absrptin f Acid Derivatives As the C=O π bnd becmes mre delcalized, adsrptin shifts t lwer frequency Cnjugatin als shifts C=O absrptin t lwer frequencies Other IR Adsrptins 1 and 2 Amines 3200-3400 cm -` (ne r tw; stretching) ~1640 cm -1 (bending) Nitrile adsrptin at 2250 cm -1 Typical NMR Signals 1H NMR α prtn signal at 2-2.5 ppm Identity f the carbnyl grup cant be determined by 1 H NMR because α hydrgen s f all acid derivatives absrb in the same range Prtns f 1 and 2 amides adsrb at 7.5-8.5 ppm 13C NMR C=O peak at 160-180 ppm C N peak at 115-120 ppm 21.2 Nuclephilic Acyl Substitutin Reactins Recall: when a nuclephile adds t an ald/ket, the initially frmed tetrahedral intermediate can be prtnated t yield an alchl When a nuclephile adds t a carbxylic acid derivative, the initially frmed tetrahedral intermediate eliminated ne f the tw substituents riginally bnded t the carbnyl carbn leads t a net nuclephilic acyl substitutin reactin Difference between ald/ket and c. acid derivative is a cnsequence f structure Carbxylic acid derivatives have an acyl carbn bnded t a grup Y than can act as a leaving grup, ften as a stable anin tetrahedral frmed, leaving grup is expelled t generate new carbnyl cmpund Ald/ket d nt have a leaving grup dn t underg substitutin Nuclephilic Acyl Substitutin is characteristic General Mechanism _ OH Oxygen Nuclephiles O OH 2 ROH R C O _ 1. Nu attacks breaks π bnd, new C-Nu bnd frms tetrahedral intermediate 2. Leaving grup eliminated, substitutin prduct made Overall: Adding Nu, eliminating Z i.e. substituting Nu fr Z; Z = -X, -OCOR, -OR, -NR 2 Nitrgen Nuclephiles NH 3 RNH 2 R 2 NH
Reactivity f Acid Derivatives Any factr that makes the carbnyl grup mre reactive tward nuclephile favrs substitutin Steric and electrnic factrs are imprtant in determining reactivity Sterically unhindered, accessible carbnyl grups react with nuclephiles mre readily than sterically hindered grups Electrnically strngly plarized acyl cmpunds react mre readily than less plar Acid Halide > Acid Anhydride > Thiester > Ester > Amide Eg/ Clride substituent is an EWG inductively withdraws electrns frm an acyl grup Eg/ Amin, methxyl and methylthi substituents dnate electrns t acyl grup What determines derivative reactivity? Leaving Grup Stability Intercnversin f Acid Derivatives Physical Prperties f Acid Derivatives C=O underges Nuclephilic Acyl Substitutin Types f Reactins Hydrlysis reactin with H 2O t yield a carbxylic acid Alchlysis reactin with an alchl t yield an ester Aminlysis reactin with ammnia r an amine t yield an amide Reductin reacatin with a hydride reducing agent t yield an ald/ket Grignard Reactin reactin with an rganmetallic reagent t yield an ald/ket 21.3 Nuclephilic Acyl Substitutin Reactins f Carbxylic Acids Cnversin f Carbxylic Acids in t Acid Chlrides Cnversin f Carbxylic Acids int Acid Anhydrides Cnversin f Carbxylic Acids int Esters S N2 reactin f a carbxylate anin with a primary alkyl halide Fischer Esterificatin starts with carbxylic acid Need t frce it Only wrks with 1 and methyl alchls
Mechanism Part A additin f nuclephile 1. Prtnatin makes C=O mre electrphilic 2. Nuclephilic additin f R OH frms tetrahedral intermediate 3. Deprtnatin fr neutral intermediate Part B eliminatin f leaving grup 4. Prtnate an OH t make gd leaving grup (H 2O) 5. Leaving grup eliminated 6. Deprtnatin fr neutral prduct ester All steps are reversible equilibrium cnstant clse t 1 reactin can be driven in either directin by reactin cnditins Ester frmatin is favred when large excess f alchl is used as slvent Carbxylic Acid frmatin is favred when a large excess f water is present Cnversin f Carbxylic Acids int Amides Cnversin f Carbxylic Acids int Alchls Bilgical Cnversins f Carbxylic Acids 21.4 Chemistry f Acid Halides Preparatin f Acid Halides Reactins f Acid Halides Hydrlysis: Cnversin f Acid Halides int Acids Cnversin f Acid Halides int Anhydrides Alchlysis: Cnversin f Acid Halides int Esters Aminlysis: Cnversin f Acid Halides int Amides Reductin and Grignard Reactin: Cnversin f Acid Chlrides int Alchls Dirgancpper Reactin: Cnversin f Acid Chlrides int Ketnes 21.5 Chemistry f Acid Anhydrides Preparatin f Acid Anhydrides Reactins f Acid Anhydrides Cnversin f Acid Anhydrides int Esters Prepare an Ester with a mre reactive acid derivative (cmpared t Fischer Esterificatin) Use milder reactin cnditins Even with less reactive alchl Cnversin f Acid Anhydrides int Amides
21.6 Chemistry f Esters Sweet smelling liquids; respnsible fr fragrant drs f fruits and flwers Preparatin f Esters Reactins f Esters Hydrlysis: Cnversin f Esters int Carbxylic Acids Hydrlysis can ccur in acid r base Under acidic cnditins the mechanism is exactly the reverse f Fischer Esterificatin (refer t mechanism abve) Base Prmted Ester Hydrlysis (sapnificatin) 1. Nuclephile attacks C=O frming tetrahedral intermediate 2. Eliminatin f leaving grup, R O - 3. Acid-base reactin between carbxylic acid and alkxide in, yields a carbxylate in 4. Additin f acid in a separate step prtnates carbxylate and gives carbxylic acid Applicatin: Lipid Hydrlysis Natural fats are triaglycerls The fatty acid esters f the tril, glycerl Ester hydrlysis is catalyzed by enzymes (lipases) The acids are usually different, R can have 11-19 C s Olestra, A synthetic fat A plyester f sucrse Steric hindrance prevents ester hydrlysis by lipases R grups cntain 11 t 19 C s Aminlysis: Cnversin f Esters int Amides RCOO RCOO O OOCR OOCR RCOO O O OOCR RCOO OOCR Base Prtnated Amide Hydrlysis 1. Nuclephile attacks C=O frming tetrahedral intermediate 2. Eliminatin f leaving grup, -NH 2 3. Acid-base reactin between carbxylic acid and amide in Applicatin: The Mechanism f Actin f β-lactam Antibitics
Penicillin interferes with synthesis f bacterial cell wall Transpeptidase enzyme frms peptide bnds t link carbhydrate chains in bacterial cell wall Enzyme reacts irreversibly with strained amide f penicillin and becmes inactive Reductin: Cnversin f Esters int Alchls Reductin f Estes (a) Using an aggressive reagent Wrk up in aqueus acid Cnverts the acyl grup t a 1 alchl Reductin f Esters (b) aldehyde intermediate can be islated if 1 equiv. f DIBAH is used as reducing agent Using a bulky reagent with nly ne hydride Cnverts the acyl grup t an aldehyde Grignard Reactin: Cnversin f Esters int Alchls Using tw equivalents f Grignard reagent Cnverts t acyl grup t a 3 alchl (same as acid chlrides)
21.7 Chemistry f Amides Amides are abundant in all living rganisms due t their stability in aqueus cnditins fund in living rganisms Amides are the least reactive f the cmmn acid derivatives and underg few nuclephilic acyl substitutin reactins Preparatin f Amides Reactins f Amides Hydrlysis: Cnversin f Amides int Carbxylic Acids Acid Prmted Hydrlysis f Amides Part A Additin f Nuclephile 1. Prtnatin makes C=O mre electrphilic 2. Nuclephilic additin f H 2O frms tetrahedral intermediate 3. Prtn transfer; NH 3 leaving grup Part B Eliminatin f Leaving Grup 4. Deprtnate an OH t push ut leaving grup (NH 3) Steps are reversible reactin needs t be frced tward prduct by prtnatin f NH 3 Heat amide at high [H + ] Basic hydrlysis (nt included in class ntes) Occurs by nuclephilic additin f OH t the amide carbnyl grup, fllwed by eliminatin f amide in (-NH 2) and subsequent deprtnatin f the initially frmed carbxylic acid by ammnia Reversible equilibrium favrs prducts by final deprtnatin f carbxylic acid Mre difficult than acid catalyzed because amide in is pr leaving grup; eliminatin step is difficult Hydrlysis f amides is initial step in digestin f dietary prteins Catalyzed by prtease enzyme Reductin: Cnversin f Amides int Amines Using an aggressive reagent and aqueus wrk-up Cnverts the amide t a 1 amine Full C=O reductin with LiAlH 4 is specific fr amides Gd way t cnvert lactam t cyclic amine
Nitrile Hydrlysis Mechanism f Nitrile Hydrlysis in Base 1. Nuclephilic Additin 2. Tautmerizatin 3. Amide Hydrlysis Mechanism f Nitrile Hydrlysis in Acid 1. Activatin and Nuclephilic Additin 2. Tautmerizatin 3. Amide Hydrlysis Practice C 4H 7O 2Br